Dual MYC and GSPT1 Protein Degrader for MYC-Driven Cancers

ABSTRACT Direct targeting of the oncoprotein MYC has long been attempted in cancer therapy, with limited success. We here identify a novel co-regulatory feedback loop of MYC and G1 to S phase transition protein 1 (GSPT1), where MYC promotes transcription of GSPT1, and GSPT1 senses stop codon of MYC to promote its translation. We report on the first-in-class dual MYC/GSPT1 protein degrader, GT19630. GT19630 significantly induced integrated stress response, abrogated oxidative phosphorylation through inhibition of the TCA cycle and induced cell death. Protein degradation of MYC was critical for efficacy of GT19630. GT19630 induced profound anti-proliferative effects and apoptosis agnostic to TP53 in a broad range of cancer cells, and is highly active in vivo in multiple, therapy-resistant hematologic and solid tumor models. Dual MYC/GSPT1 degradation was well tolerated in humanized Crbn I391V mice. In conclusion, we propose a novel treatment approach by directly targeting the MYC-GSPT1 axis in MYC-driven cancers. Statement of significance MYC has been considered an undruggable protein. We found a targetable, novel positive co-regulatory feedback of MYC and GSPT1, a key translation terminator. The dual MYC/GSPT1 degrader GT19630 is highly active in MYC-driven tumors, with moderate effects on humanized Crbn mice, providing opportunities to improve treatment outcome of MYC-driven cancers.